Many hormones and neurotransmitters regulate vital functions through specific receptors existing in cell membranes.
Many of these receptors conduct intracellular signaling through the activation of coupled guanine nucleotide-binding protein (as may be hereafter abbreviated to “G-protein”). Also, these receptors are collectively called G-protein-coupled receptors (GPCR) or 7 trans-membrane receptors (7TMR), as they have common structures having seven trans-cytomembrane domains.
As one of such G-protein-coupled receptors, a human receptor protein coded by CXCR4 gene is known [Journal of biological chemistry, Vol. 273, 4754 (1998)].
Also, CXCL12/SDF-1α, which is a physiologically active peptide functioning as a ligand of the above-mentioned CXCR4, is known [Science, Vol. 261, 600-603 (1993)].
Certain peptidic compounds having antagonistic action against CXCR4 are disclosed and their anti-HIV activity is described in Fujii, International Publication WO02/20561 Mar. 14, 2003.
Cancer metastasis is one of the critical factors affecting the life expectancy of patients. It is reported that the expression of CXCR4 is enhanced in breast cancer cells, etc., and that the expression of CXCL12/SDF-1α which is a ligand of CXCR4 is enhanced in cancer-metastasized organs (lymph nodes, lungs, livers and bones) [Nature, Vol. 410, 50-56 (2001)]. Also, in chronic rheumatoid arthritis, the infiltration of CD4 positive mermory T-cells into articular cavity fluids affects the progression of the conditions. It is reported that in CD4 positive T-cells in articular cavity fluids of patients suffering from chronic rheumatoid arthritis, the expression of CXCR4 genes is enhanced, and that the expression of CXCL12/SDF-1α genes is enhanced in articular synovial membrane tissues [Journal of Immunology, Vol. 165, 6590-98 (2000)].
The present invention aims at providing novel means using CXCR4 antagonistic compounds for the prevention and/or therapy of cancers and chronic rheumatoid arthritis. Also, the present invention provides novel compounds, in particular, various oligopeptides with common structures, which have preventive and/or therapeutic activity for cancers and chronic rheumatoid arthritis.